PROJECT 1 - PROJECT SUMMARY / ABSTRACT Alzheimer's disease (AD), an age associated neurodegenerative disorder, is pathologically characterized by plaques consisting of aggregated beta-amyloid (A?) and intracellular neurofibrillary tangles (NFT) formed by hyperphosphorylated tau. A? is formed by the sequential action of ? and ? secretase on the C-terminal side of amyloid precursor protein (APP). Oxidative stress has been implicated in human AD patients and several studies have shown A?-mediated oxidative stress to be central to the AD pathogenesis and progression. In addition to, or associated with oxidative stress, a reduction/dysfunction of autophagy is observed in AD. Autophagic vacuoles (AVs) that are rarely observed in neurons of healthy individuals are found to accumulate in the dystrophic and less affected neuritis in AD. Indeed, autophagy is hypothesized to be a major mechanism mediating APP turnover normally and generation of intracellular A? when dysfunctional. NF-E2- related factor 2 (Nrf2) has been implicated to be involved, not only in mitigating oxidative stress, but also an important factor in regulating and responding directly and indirectly to the changes in autophagy in vivo and in vitro. There is little work examining the role of Nrf2 in APP processing/turnover and A? production/degradation in AD with no information existing in the animal models of AD or human AD tissue. Recently, data from our laboratory found that overexpression of Nrf2 in astrocytes (GFAP-Nrf2) dramatically delays autophagic dysfunction in neurons of alpha synuclein A53T mice. This correlated with a highly significant delay in disease onset and extension of lifespan. Initial crosses of our GFAP-Nrf2 mice with APP/PS1 mice demonstrate a reduced plaque density and a dramatic reduction in intracellular APP or cleavage products. Thus, the specific aims of this proposal are: Aim 1. To determine the effect of astrocytic Nrf2 overexpression on APP processing/turnover and A? production/degradation in APP/PS1 mice. Aim 2. To elucidate the mechanism involved in astrocytic Nrf2-mediated changes in APP processing/turnover and A? production/degradation in astrocyte-neuron cultures derived from APP/PS1 mice. Aim 3. To determine changes in astrocytic Nrf2 activation in possible/early and definitive/late stage human AD brain. Completion of the proposed studies will solidify the significance of astrocytic Nrf2 activation as a modulator of AD pathology.